Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB).

Five novel analogs of 6-(ethyl)(4-isobutoxy-3-isopropylphenyl)amino)nicotinic acid-or NEt-4IB-in addition to seven novel analogs of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism alongside bexarotene (1), a FDA-approved drug for cutaneous T-cell lymphoma (CTCL). Bexarotene treatment elicits side-effects by provoking or disrupting other RXR-dependent pathways. Analogs were assessed by the modeling of binding to RXR and then evaluated in a human cell-based RXR-RXR mammalian-2-hybrid (M2H) system as well as a RXRE-controlled transcriptional system. The analogs were also tested in KMT2A-MLLT3 leukemia cells and the EC50 and IC50 values were determined for these compounds. Moreover, the analogs were assessed for activation of LXR in an LXRE system as drivers of ApoE expression and subsequent use as potential therapeutics in neurodegenerative disorders, and the results revealed that these compounds exerted a range of differential LXR-RXR activation and selectivity. Furthermore, several of the novel analogs in this study exhibited reduced RARE cross-signaling, implying RXR selectivity. These results demonstrate that modification of partial agonists such as NEt-4IB and potent rexinoids such as bexarotene can lead to compounds with improved RXR selectivity, decreased cross-signaling of other RXR-dependent nuclear receptors, increased LXRE-heterodimer selectivity, and enhanced anti-proliferative potential in leukemia cell lines compared to therapeutics such as 1.

Amisulpride: A New Drug for Management of Postoperative Nausea and Vomiting.

OBJECTIVE: To review the pharmacology, efficacy, and safety of amisulpride and determine its role in the management of postoperative nausea and vomiting (PONV). DATA SOURCES: A PubMed search (1946 to November 2020) using the terms amisulpride and APD421 was conducted. STUDY SELECTION AND DATA EXTRACTION: Relevant reports on intravenous amisulpride were included. DATA SYNTHESIS: Six clinical trials were evaluated. In 4 trials on the prevention of PONV, a greater percentage of patients who received amisulpride 5 mg compared with placebo experienced a complete response (44%-60% vs 31%-33%, respectively, when used as monotherapy; 58% vs 47%, respectively, when used in combination with another antiemetic). In 2 trials on the treatment of PONV, a significantly greater percentage of patients who received amisulpride 10 mg compared with placebo experienced a complete response (31.4% vs 21.5%, respectively, in patients who had not received prophylaxis; 41.7% vs 28.5%, respectively, in patients who had received prophylaxis). Adverse effects included infusion site pain, chills, hypokalemia, procedural hypotension, and abdominal distension. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Amisulpride is effective for the management of PONV and may be less likely to cause QT prolongation and extrapyramidal symptoms than other dopamine antagonists. Additional information is needed on its use for chemotherapy-induced nausea and vomiting and in children. CONCLUSIONS: Amisulpride is an important new option for the multimodal management of PONV in adults, and it may be the preferred dopamine antagonist because of the more favorable safety profile that results from its unique pharmacological properties.